Post on 15-Jan-2023
Table of contents
1. Introduction………………………….…………..1
1.1. Single Unit Dosage Forms……………………3
1.2. Multiple Unit Dosage Forms…………………3
1.3. Why MUPS Technology?.................................5
1.4. Multiparticulates…………………………….11
1.5. Pelletization Techniques…….………………13
1.6. Coating of Pellets…………………………….19
2. Objectives………………………………………..24
3. Review of Literature……………………………..27
4. Methodology…………………………………….35
5. Results……………………………….…………...69
6. Discussions………………………………………84
7. Summary………………………………………….88
8. Conclusion………………………………………..92
9. Bibliography………………………………………93
10.Annexure………………………………………….99
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V. Mridula, Dept. of Pharmaceutics Page 1
1. INTRODUCTION
From many decades, conventional dosage forms, which are of prompt releasing nature
are used for treatment of acute and chronic diseases.
The conventional dosage forms provide no control over release of drug
To maintain the drug1 concentration within the therapeutically effective range it is often
necessary to take these types of conventional dosage forms several times a day. This
results in significant fluctations in drug levels.
The term “sustained action”2 is known to have existed in the medical and pharmaceutical
literature for many decades. It has been constantly used to describe a pharmaceutical
dosage form formulated to retard the release of a therapeutic agent such that its
appearance in the systemic circulation is delayed and / or prolonged and its plasma
profile is sustained in duration. The onset of its pharmacological action is often delayed
and the duration of its therapeutic effect is sustained.
1.The concept of sustained action is prolonged release of biologically active agents has
been well-appreciated and rationalized for decades.
In the field of pharmaceuticals, sustained release systems have been widely used in oral
medication, since early 1950s. Perhaps the earliest examples are enteric-coated orally
ingested tablets. Other slow release systems include encapsulated pellets or beads,
sparingly soluble salts, complex system, drug embedded in matrix, ion exchange resins,
and swelling hydro gels. Most of the early products can be classified under sustained
delivery systems, which means the release of active agent is slower than any conventional
formulation, but it is significant effected by external environment. The therapeutic range
and duration of action of drugs are important for consideration in drug therapy.
Therefore, sustained release products have received substantial attention in recent years.
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2. A multiple unit dosage form could readily separate into sustained release units
throughout the gastrointestinal (GI) tract after ingestion.
One of the multiple unit dosage forms is the pellet, which reduces variation in gastric
emptying time and transit time, is less susceptible to dose dumping, and provides less
irritation from high local concentration of drugs.
3. Oral sustained action dosage forms are widely used for delivery of medicament. The
dosage forms can be categorized based on number of unit per dosage into single and
multiple unit dosage forms. The multiple unit dosage forms are preparations that consist
of several mini reservoirs.
Pellets3 or microencapsulated crystals filled in capsules or compressed into fast
disintegrating tablets are multiple unit dosage forms, which offer several advantages over
single unit dosage forms, such as independence of gastric emptying rate, increase in
Bioavailability 4, reduction in side effects, and possibility of combining incompatible
drugs in a single unit.
4. Pellets offer a high degree of flexibility in the design and development of oral dosage
forms. They can be divided into desired dose strengths without formulation or process
changes and also can be blended to deliver incompatible bioactive agents simultaneously
and/or to provide different release profiles at the same or different sites in the
gastrointestinal tract. In addition, pellets, taken orally, disperse freely in the GI tract
maximize drug absorption, minimize local irritation of the mucosa by certain irritant
drugs, and reduce inter and intra patient variability.
5. Pellets are spherical agglomerated powders and can be prepared by various processes
thus mechanism of pellets formations and not alike.
Pelletization techniques widely used in pharmaceutical industries are direct pelletization
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V. Mridula, Dept. of Pharmaceutics Page 3
extrusionspheronization 5 and layering. Direct pelletization technique using fluidized
bed equipment has many advantages such as one-unit process no starting material
required and short processing time.
6. The layering technique is the process in which drug in powder solution, or suspension
form is layered onto seed materials. Layering can be carried out in either conventional or
fluidized bed equipment. The latter offers much advantage such as one unit process,
higher yields, higher reproducibility, and good control over process parameters.
Therefore, the fluidized bed process is of interest and gains popularity in pellet
manufacturer.
1.1. Single Unit Dosage Forms:
The single-unit dosage forms usually refer to diffusion controlled systems which
include monolithic systems 6, where the diffusion of a drug through a matrix is the rate-
limiting step , reservoir or multilayered matrix systems, where the diffusion of the drug
through the polymer coating or layer of the system is the rate-limiting step. However,
generally, release of drugs will occur by a mixture of these two mechanisms .
Capsules can also be used as single-unit delayed-release delivery systems .
1.2. Multiple Unit Dosage Forms:
Multiparticulates as dosage forms have been known since the 1950s when the first
product was introduced to the market. Since then, these dosage forms have gained
considerable popularity because of their distinct advantages such as ease of capsule
filling, better flow properties of the spherical beads, ease of coating, sustained, controlled
or site-specific delivery of the drug from coated beads, uniform packing, even
distribution in the GI tract, and less GI irritation. In addition, beads are less susceptible to
dose dumping, which results in reduced peak plasma fluctuations, thus minimizing the
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potential side effects without appreciably lowering drug bioavailability.
Types of multiple unit dosage forms comprise
• Pellets
• Granules
1.2.1. Mechanism of drug release:
The mechanism of drug release from multiparticulates can be occurring in the following
ways:
• Diffusion: On contact with aqueous fluids in the gastrointestinal tract (GIT), water
diffuses into the interior of the particle. Drug dissolution occurs and the drug solutions
diffuse across the release coat to the exterior.
• Erosion: Some coatings can be designed to erode gradually with time, thereby releasing
the drug contained within the particle
• Osmosis: In allowing water to enter under the right circumstances, an osmotic pressure
can be built up within the interior of the particle. The drug is forced out of the particle
into the exterior through the coating
Multiparticulate dosage forms can be prepared by a number of techniques such as drug
layering on non-pareil sugar or microcrystalline cellulose beads,7 spray-drying, spray
congealing, rotogranulation, hot-melt extrusion8 and spheronization of low melting
materials or extrusion-spheronization of a wet mass. Beads can also be either coated with
rate-limiting polymers or compressed into tablets to obtain slow-release, target-release or
controlled-release profiles.
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1.3. WHY MUPS TECHNOLOGY?
Multi-particulate drug delivery systems are mainly oral dosage forms consisting of
multiplicity of small discrete units, each exhibiting some desired characteristics. In these
systems, the dosage of the drug substances is divided on a plurality of subunit, typically
consisting of thousands of spherical particles with diameter of 0.05-2.00 mm. Thus
multiparticulate dosage forms are pharmaceutical formulations in which the active
substance is present as a number of small independent subunits. To deliver the
recommended total dose, these subunits are filled into a sachet and encapsulated or
compressed into a tablet.
Multiparticulates are discrete particles that make up a multiple-unit system.
They provide many advantages over single-unit systems because of their small size.
Multiparticulates are less dependent on gastric emptying, resulting in less inter and intra-
subject variability in gastrointestinal transit time. They are also better distributed and less
likely to cause local irritation. Recently much emphasis is being laid on the development
of multiparticulate dosage forms in preference to single unit systems because of their
potential benefits such as increased bioavailability, reduced risk of systemic toxicity,
reduced risk of local irritation and predictable gastric emptying. There are many reasons
for formulating drug as a multiparticulate system for example, to facilitate disintegration
in the stomach, or to provide a convenient, fast disintegrating tablet that dissolves in
water before swallowing which can aid compliance in older patients and children
Multiparticulate systems show better reproducible pharmacokinetic9 behavior than
conventional (monolithic) formulations. After disintegration10 which occurs within a few
minutes often even within seconds, the individual subunit particles pass rapidly through
the GI tract. If these subunits have diameters of less than 2mm, they are able to leave the
stomach continuously, even if the pylorus is closed. These results in lower intra and inter
individual variability in plasma levels and bioavailability. Drug safety may also be
increased by using multiparticulate dosage forms, particularly for a modified release
systems. For example, if the film coat of a single-unit (monolithic) enteric coated tablet is
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damaged, the complete dose will be released into the stomach where it may cause pain or
ulceration or reduced efficacy, depending on the reason for choosing the protection of the
enteric coating. Equally, if there is damage to the film coating of a monolithic tablet with
a sustained release formulation, this can lead to “dose dumping” and result in dramatic
side effects. By contrast, in multiparticulate formulation, the release characteristics are
incorporated into every single subunit and any damage only affects the release behavior
of the subunit involved, which represents a small part of the total dose, reducing the
likelihood of safety problems.
1.3.1 Approaches to MUPS:
Multiparticulates approaches tried for colonic delivery includes formulations
in the form of pellets, granules, microparticles and Nanoparticles. Because of their
smaller particle size compared to single unit dosage forms these systems are capable of
passing through the GI tract easily, leading to low inter and -intra subject variability.
Moreover, multiparticulate systems are to be more uniformly dispersed in the GI tract and
also ensure more uniform drug absorption11.
Multiparticulates may be prepared by several methods. Different methods
require different processing conditions and produce multiparticulates of distinct qualities.
Some of these methods may be broadly classified as pelletization12, granulation, spray
drying, and spray congealing. Drug particles may be entrapped within the
multiparticulates or layered around them. Subsequently, these multiparticulates may be
modified in many ways to achieve the desired drug release profile. One approach to the
modification of drug release profile in multiparticulates is to coat them. Reasons for the
application of coating onto multiparticulates are to obtain functional coats, provide
chemical stability, improve physical characteristics and enhance patient acceptance.
Coats are formed from various polymeric coating materials broadly classified as aqueous
polymer dispersions, polymer solutions, molten polymers and dry powders. Depending
on the type of coating material used, functions such as sustained release (SR), targeted
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release, delayed release, and pulsatile release can be achieved. The most common method
used for the application of coating onto multiparticulates is air suspension coating. Other
methods include compression coating, solvent evaporation13, coacervation, and interfacial
complexation. It is also possible to form coated multiparticulates by spray drying and
spray congealing. A multiparticulate composition may allow controlled release of the
drug over a wide range of release rates, and permit the release rate to be set at a
predetermined rate, such a formulation may be formed using a melt-congeal process
which maintains the crystallinity of the drug during the melt-congeal process. A
multiparticulate delayed release system based on coated pellets containing an osmotic
active ingredient has been prepared. Following ingestion water penetrates into the core
and forms a saturated solution of the soluble components. The osmotic pressure gradient
induces a water influx resulting in a rapid expansion of the membrane leading to the
formation of pores. The osmotic ingredient and the drug are released through these pores
according to zero order kinetics. In comparison with the sodium chloride free formulation
the inclusion of the osmotically active ingredient results in a completely different
dissolution behavior. Lag time and dissolution14 rate were dependent on the coating level
and the osmotic properties of the dissolution medium.
Multiparticulate15 drug delivery systems are mainly dosage forms consisting of large
number of small discrete units each exhibiting desirable characteristics. Multiparticulates
may be prepared by different methods like pelletization, granulation, spray drying and
spray congealing. Drug particles may be entrapped within the multiparticulates (matrix
systems) or layered around them (Reservoir systems). They can be modified in many
ways to achieve desired drug release profile. Depending on the type of coating material
used, sustained release, delayed release, targeted release and pulsatile release can be
obtained in addition to improvement of chemical stability, physical characteristics and
patient acceptance. The purpose of designing multi particulate drug delivery system is to
develop a formulation with all the advantages of single unit formulations. Various
techniques like spheroidal oral drug absorption systems (SODAS), programmable oral
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drug absorption systems, pelletized delivery system, and pelletized tablet systems were
developed. In spheroidal oral drug absorption system, the beads are coated with different
types of product specific polymers and encapsulated into a hard gelatin capsule. By
combining different beads, varying degrees of controlled release profiles can be obtained.
In pelletized delivery system, sustained release beads are manufactured by different
techniques like spheronization and coated with release modulating polymers. Later, the
coated beads are filled into hard gelatin capsules.. Pellets offer various advantages over
other systems like less patient compliance, high dose strength administration, and high
production rate and no taste compliance over tablets.. The other major advantages are
reduced risk of local irritation and toxicity, predictable bioavailability, minimized
fluctuations in plasma concentration of drug caused by food effects.
Ideal characters for coating of pellets:
Nature of Polymer16: The polymer used in preparation of pellet plays an important role
in drug release. It must have sufficient elastic properties to prevent rupture of coating
polymer and plastic properties to accommodate the changes in shape and deformation.
Ethyl cellulose possesses weak mechanical properties and hence the pellets compacted
with ethyl cellulose showed loss of sustained properties. Use of pseudo latexes
plasticized ethyl cellulose showed minimal effect on mechanical properties of ethyl
cellulose making it brittle with low values of puncture strength and elongation.
The coatings prepared from organic solvents of ethyl cellulose were more
resistant to compaction compared to that of aqueous solutions. The films formed byusing
organic solvents showed better mechanical properties. To reduce the damage to coating,
compressed pellets can be kept in hot air oven above the glass transition temperature
which resulted in covering of ruptures due to compression. Brittle character of ethyl
cellulose can be overcome by using multilayered beads consisting of alternating layers of
ethyl cellulose, drug or cushioning agent.
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Crystals, granules or pellets coated with aqueous acrylic polymer dispersions (Eudragit NE 30D, Eudragit RS/RL 30D) were more flexible than ethyl cellulose films
and they can be compressed with little damage to the coating
Thickness of polymer coating17: - In general, a thicker coating can prevent damage due
to compression than the thinner coating. The deformation characteristics changed with
the increased coating. Ability of pellets to undergo plastic deformation as well as elastic
deformation increased with increasing coating level. However, an increased coating level
caused decrease in tensile strength, yield pressure and increased elastic recovery on
ejection. Increasing the punch velocity resulted in decrease in tensile strength of the
compacts and increase in both yield pressure and elastic recovery values. The punch
velocity dependence increased with increased coating levels.
Pellet Core18: - Not only the film but also the core of pellet should also have sufficient
flexibility. It must possess some degree of elasticity, which can accommodate changes in
shape and deformation. It should deform and recover after compression without damage
to the coating. . Compactability of lactose rich pellets was better than that of micro
crystalline cellulose pellets. The poor compactability of micro crystalline cellulose
pellets is due to loss of plasticity during wet granulation process. Lactose/micro
crystalline cellulose beads were more compressible and exhibited more fracture than
micro crystalline cellulose beads..
Porosity19: -Increased pellet porosity increased the degree of deformation of pellets
during compression and tensile strength of tablets because of formation of stronger inter-
granular bonds. The effect of intragranular porosity on drug release is also high.
Compacted pellets of high porosity were densely packed and deformed. So the drug
release was unaffected. The drug release was markedly increased when low porosity
pellets were compacted due to slight densification and deformation. So the use of highly
porous pellets was advantageous, in terms of preserving the drug release profile.
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Size: - The size of the pellets also affects compaction properties and drug release from
the compacted pellets. At the same coating level, smaller pellets were more fragile than
larger pellets. This is due to the reason that increased surface area resulted in reduced film thickness . It was also found that increase in particle size resulted in more damage
to the coating, as indicated by larger difference between the release profile of tablets and
uncompressed pellets
Shape: - shape of the pellets was found to affect the compression behavior and tablet
forming ability of granular materials. More irregular shape induced more complex
compression behavior of granules i.e., more attrition of the granules was induced and
increased deformation was resulted. Isometric shaped pellets offer less contact points and
uniform drug release when compared with anisometric shaped particles.
Density: - Density of pellet is required to achieve prolonged gastric residence. The
critical density to achieve prolonged gastric residence may lie between 2.4 to 2.8g/cm3
Density and size of the pellets play an important role for achieving content and weight
uniformity. Segregation may occur when pellets are compressed using excipients with
smaller particle size and density.
Use of pellets with a narrow size distribution along with excipients of similar size,
shape and density can prevent seggregation.
Hardness of Pellets: - Harder pellets coated with Eudragit L30 D-55 were able to
resist the compression forces better when compared with softer, more porous pellets, which deform easier and therefore resulted in a higher degree of film rupture.
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1.4. MULTIPARTICULATES
Multiple unit dosage forms are essential where drug-excipients or drug-drug
physicochemical interaction is possible in a single-unit formulation. They are also known
to have less variance in transit time through the gastrointestinal tract than single-unit
dosage forms. They are usually delivered in hard gelatin capsules or made into tablets
that disintegrate instantly.
1.4.1. PELLETS
Pharmaceutical pellets are agglomerates of fine powder particles or bulk drugs and
excipients, small, free-flowing, spherical or semi-spherical solid units, size ranges from
about 0.5mm to 1.5mm (ideal size for oral administration) , obtained from diverse
starting materials utilizing different processing techniques and conditions
1.4.1.1. Desirable properties of pellets:
Uncoated pellets:
• Uniform spherical shape and smooth surface
• Optimum size, between 600 and 1000μm
• Improved flow characteristics
• High physical strength and integrity
• Good hardness and low friability
• High bulk density20
• Ease and superior properties for coating
Coated pellets:
• Maintain all of the above properties.
• Contain as much as possible of the active ingredient to keep the size of the final
dosage form within reasonable limits
• Have desired drug release characteristics.
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Figure 1: (a) Pellets, (b) Perfect pellet, (c) Coated pellet
1.4.1.2. Advantages of pellets
• The smooth surface and the uniform size of the pellets allow uniform coating not only
for each pellet but also from batch to batch. Coating of pellets can be done with
different drugs to enable a controlled release rate.
• In case of immediate release products, larger surface area of pellets enables better
distribution.
• Chemically incompatible products can be formed into pellets and delivered in a
single dose by encapsulating them.
• The beads or granules of different thickness of coatings are blended in the desired
proportions to give the desired effect.
• The thickness of the coat on the pellets dictates the rate at which the drug or contents
are released from the coated particles.
• By selecting the proper formulation, processing conditions and processing equipment,
it is possible to attain smooth surfaced and uniform pellets.
Improved appearance of the product and the core is pharmaceutically elegant
• Pellets can be divided into desired dosage strength without process or formulation
changes and also allows the combined delivery of two or more bioactive agents that
may or may not be chemically compatible, at the same site or at different sites within
the gastrointestinal tract.
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• They offer high degree of flexibility in the design and development of oral dosage
form like suspension, tablet and capsule.
Recently, coated pellets are compressed to rapidly disintegrating tablets. For this purpose
small pellets with the mean diameters below 0.5 mm are most suitable. Such pellets can
be produced by direct pelletization methods
1.4.1.3. Disadvantages of pellets:
• The manufacturing of multiple unit dosage forms is more complicated and more
expensive.
• The filling into gelatin capsules is difficult to accomplish, especially in the case where
different subunits are involved.
1.5. PELLETIZATION TECHNIQUES21
Pelletization is an agglomeration process that converts fine powders or granules of
bulk drugs and excipients into small, free-flowing, spherical or semi-spherical units,
referred to as pellets. The type of coating technique strongly affects the film
microstructure and thus affects the release mechanism and rate from pellets coated with
polymer blends. There are several manufacturing techniques for production of spherical
pellets.
1.5.1. AGITATION22
1.5.1.1. Balling: Finely divided particles are converted upon the addition of appropriate
quantities of liquid, to spherical particles by a continuous rolling or tumbling motion.
Pans, discs, drums, or mixers may be used to produce pellets by the balling.
1.5.2. COMPACTION
1.5.2.1. Compression: Mixtures or blends of active ingredients and excipients are
compacted under pressure to generate pellets of defined shape and size.
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1.5.2.2. Extrusion – Spheronization: It is a multistep process invented by Nakahara, in
1964, involves dry mixing of the active compound with excipients, granulation of wetted
mass, extrusion of the mass, transfer of the mass to spheronizer to produce spherical
shape, drying of the wetted mass in a dryer, and at the end screening to obtain required
particle size.
Figure 2: Principle of Extrusion – Spheronization process
1.5.3. LAYERING23
In this process, drug is layered onto seed materials (generally, a coarse material or
nonpareil) in powder, solution or suspension form and leads to heterogeneous pellets,
which consist of an inner core region and an outer shell region of a different composition.
This process is classified into three categories namely direct pelletization, solution or
suspension layering and powder layering.
1.5.3.1. Direct pelletization:
A process that leads to formation of homogeneous pellets which have
microscopically uniform structure and no core can be detected. Direct pelletization is
mainly performed in high shear mixers and fluidized bed equipment .
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Figure-3 Direct pelletization
1.5.3.2. Powder Layering24
Powder layering involves the deposition of successive layers of dry powder of
drug or excipients or both, on preformed nuclei or cores with the help of a binding liquid.
Equipment used is tangential spray/centrifugal/rotary fluidized bed granulator .
Some of the disadvantages are:
• Low amount of drug loading which is not suitable for high-dose drugs
• Final composition of pellets can vary if spray loss occurs.
Figure 4: Principle of Powder layering process\
1.5.3.3 Solution/Suspension layering25
In the case of Solution/Suspension layering, growth of pellets involve deposition
of successive layers of solution and/or suspension of drug substance and binders on
existing nuclei, which may be inert seed, crystal or granule. The drug particles are
dissolved or suspended in the binding liquid, with or without the binder. Droplets of the
binding liquid spread on the surface of the nuclei. During drying, liquid evaporates and
the dissolved substances crystallize out and capillary forces which are formed draw the
particles towards each other and towards the inert seed, forming solid bridges. In
suspension layering, particles have low solubility and are bonded by solid bridges formed
from the hardening binder i.e., that higher concentration of binder might be necessary.In
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this process fines are produced as a result of attrition or spray drying especially when the
process is not optimized .
The efficiency of the process and the quality of pellets produced are in part related
to the type of the equipment used.
As a starter seeds usually sugar spheres consisting of a sugar-starch mixture or
recently microcrystalline cellulose pellets and the pure drug crystals are used.
The most common configuration used is Wurster26, bottom spray coater.
This technology is applied to produce enteric coated multiple unit pellets for
improving the stability in acidic media, due to the enhancement of the polymer film
formation on the surface of the pellet. On the other hand enteric coating assures.
Immediate release of alkali media at the time of the release.
Figure 5: Principle of Solution and Suspension layering process
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Mechanism involved in coating of pellets by Wruster process
The Wurster process is a coating technique that is well
suited to uniformly coat or encapsulate individual
particulate materials. This technology is characterized by
the location of a spray nozzle at the bottom of a fluidized
bed of solid particles. The particles are suspended in the
fluidizing air stream that is designed to induce a cyclic
flow of the particles past the spray nozzle. The nozzle
sprays an atomized flow of coating solution, suspension, or
other coating vehicle.
The atomized coating material collides with the particles as
they are carried away from the nozzle. The temperature of
the fluidizing air is set to appropriately evaporate solution
or suspension solvent or solidify the coating material
shortly after colliding with the particles.
All coating solids are left on the particles as a part of the
developing film or coating. This process is continued until
each particle is coated uniformly to the desired film
thickness.
The Wurster process is an industry recognized coating
technique for precision application of film coat to particulate materials such as
powders, crystals, or granules. The technology can be used to encapsulate solid
materials with diameters ranging from near 50µm to several centimeters. The process
has a greater drying capacity than other coating systems due to a relatively high
fluidizing air velocity. Since the particles actually separate as they are carried away
Fig:6 schematic
representation of
wruster process
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from the nozzle, it is possible to coat small particles without agglomeration. Coating
possibilities are relatively unlimited including the ability to place a hydrophilic coat on
a hydrophobic core, or a water-based coat on a water-soluble core. Coating properties
can be optimized with coat formulation parameters, processing conditions, and
layering.
Fig: 7 Process principle of fluid bed coating
1.5.4. GLOBULATION27:
Globulation or droplet includes spray drying and spray congealing
1.5.4.1. Spray drying28:
Drug entities in solution or in suspension form are sprayed, with or without excipients,
into a hot air stream to generate dry and highly spherical particles. It is generally
employed to improve the dissolution rates and hence, bioavailability of poorly soluble
drugs
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1.5.4.2. Spray congealing29:
A process in which a drug is allowed to melt, disperse, or dissolve in hot melts of gums,
waxes, fatty acids, etc., and is sprayed into an air chamber where the temperature is
below the melting points of the formulation components, to provide spherical congealed
pellets under appropriate processing conditions.
1.6. COATING OF PELLETS
The application of coating is usually based on one or more of the following:
• To mask the taste, odor or color of the drug.
• To provide physical and chemical protection to the drug.
• To control the release of the drug.
• To protect the drug from the gastric environment of the stomach with an acid resistant
coating.
• To incorporate another drug or formula adjuvant in the coating to avoid chemical
incompatibility or to provide sequential drug release.
• To provide pharmaceutical elegance by use of special color.
Types of Coating
1. Drug coating
2. Sub coating
3. Enteric coating
4. Cushion coating
5. Film coating
Film coating30
V. Mridula, Dept. of Pharmaceu
There are numerous
formulations; for example,sus
aim of this paper was to stud
coatings in a fluid-bed proces
thickness formed. Eight pellet
and the other batches can b
cylinders. The average coa
measurements did not appear
fluid-bed process, however, h
ratio greater than 1.5. The ch
monitored effectively employi
shape occurred at the beginni
min, after which the shape rem
DRUG PROFILE
TELITHROMYCIN
IUPAC1S,2R,5R,7R,8R,9S,11R,13R,14-dimethylamino-3-hydroxy-62-ethyl-9-methoxy-1,5,7,9,11,[4-(4-pyridin-3-ylimidazol-1-yazabicyclo[12.3.0]heptadecane
STRUCTURE
Molecular formula -C43H65N
Telithrom
utics
reasons for which film coatings are ap
stained action taste masking, and improve
dy the influence of pellet shape on the dep
ss by monitoring the pellet shape as a func
t batches were used, of which four were sph
be described as ovoids, dumbbells, long
at thickness of the pellets assessed by
r to be influenced by the initial shape of t
ad an impact especially for those pellets tha
ange in the pellet shape during film coating
ing a three-dimensional shape factor. Signifi
ing of the coating process up to approximat
mained constant.
4R)-8-[(2S,3R,4S,6R)-6-methyl-oxan-2-yl]oxy-13-hexamethyl-15-yl)butyl]-3,17-dioxa-15-e-4,6,12,16-tetrone
TELITHROMYCINN5010
mycin Pellets
Page 20
pplied to pellet
d stability. The
position of film
tion of the film
herical visually,
dumbbells, and
y cross-section
the pellets. The
at had an aspect
g could only be
icant changes in
tely the first 15
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 21
Molecular mass -812.004G/MOLMolecular weight -1178.8412
PHYSICOCHEMICAL CHARACTERISTICS
Description-white colour
Odor-odorless
Solubility-good water solubility.it is soluble in ethanol,methanol
Melting point-176-188c
Boiling point-966.2c at 760 mmhgFlash point-538.2c
Half life-10 hours
Mechanism of action31
Telithromycin prevents bacteria from growing, by interfering with their protein synthesis.
Telithromycin binds to the subunit 50s of the bacterialribosome, and blocks the progression of the growing polypeptide chain. Telithromycin has over 10 times higher
affinity to the subunit 50S than erythromycin. In addition, telithromycin strongly bind
simultaneously to two domains of 23S RNA of the 50 S ribosomal subunit, where older
macrolides bind strongly only to one domain and weakly to the second domain.
Telithromycin can also inhibit the formation of ribosomal subunits 50S and 30s
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TELITHROMYCIN PATHWAY
Pharmacokinetics
ABSORPTION
Drug is mainly absorbed through tissues.
Its bioavailability is 57%
DISTRIBUTION32
Protein binding takes place 60-70%bound primarily to human serum albumin
Volume of distribution -2.91/kg
METABOLISM33
Telithromycin is mainly metabolized in liver
EXCRETION
It is through biliary and renal route.
ADVERSE EFFECTS
Gastrointestinal, including diarrhea, nausea, abdominal pain and vomiting. Headache and
disturbances in taste also occur. Less common side-effects include palpitations, blurred
vision, and rashes. Prolonged QTc intervals may also be caused by Telithromycin.
Drug interactions34
1..Telithromycin may increase the anticoagulant effect of acenocoumarol.
2. Telithromycin may reduce clearance of Alfentanil. Consider alternate therapy or
monitor for changes in the therapeutic/adverse effects of Alfentanil if Telithromycin is
initiated, discontinued or dose changed.
3. Telithromycin may reduce clearance of Alfuzosin. Consider alternate therapy.
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4. Telithromycin may increase the effect and toxicity of the benzodiazepine, alprazolam.
5.Telithromycin may reduce clearance of Ambrisentan. Consider alternate therapy or
monitor for changes in the therapeutic/adverse effects of Ambrisentan if Telithromycin is
initiated, discontinued or dose changed.
6. Aminoglutethimide may decrease the plasma concentration of Telithromycin. Consider alternate therapy.
7. Telithromycin may reduce clearance of Amiodarone. Consider alternate therapy or
monitor for changes in the therapeutic/adverse effects of Amiodarone if Telithromycin is
initiated, discontinued or dose changed.
APPLICATIONS
1. Telithromycin is used to treat certain types of pneumonia (an infection of the lungs)
2. that is caused by bacteria.
3. Telithromycin is in a class of medications called ketolide antibiotics.
4. It works by killing bacteria. Antibiotics will not kill viruses that can cause colds, flu, or other infections.
5. It is a novel drug which shows high potency.
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2 OBJECTIVES
Researchers to modulate and release the drug over an sustained period of time have
devised many drug delivery systems. The majority of these systems are and their
principal drug release mechanism is based on the drug diffusion through the matrix
system. The diffusion is altered by the pH35 of the medium, the presence of food, and the
body’s physiological factors, all of which cause difficulty in controlling the drug release
rate. Another delivery method used is the ‘pellet’. Selected dosage forms use the
principles of diffusion, erosion, and surface desorption, and combination of
diffusion,erosion36 and dissolution.
The objectives of the present investigations are:
1 .Preparation of Telithromycin sustained release pellets using different polymers
different techniques.
2. Characterization of telithromycin pellets.
3. In vitro37 evaluation of telithromycin pellets for the release characteristics.
4. To study the physic-chemical parameters of drug release from multiparticulate system.
5. To study the predetermined rate of drug release38.
6. To study the preformulation39 characteristics.
A survey of the literature indicates that extensive work was conducted in the
development of sustained release dosage forms. The drugs studied are Erythromycin
Theophylline,Zyban, Metformin hydrochloride, Terbutaline sulphate, Aceclofenac etc.
Many attempts were made to develop sustained release dosage forms to release the drugs
for an extended period of time.The drug release mechanism from such a system may
explained by the following dissolution ,erosion, surface desorption, combination of
diffusion and erosion. Hence, in the present proposed work, sustained release pellets of
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telithromycin were planned on the principles of sustained release dosage forms. Further,
an attempt was made to develop sustained release dosage form with zero order release
TELITHROMYCIN
Telithromycin is the novel ketolide antibiotic.
Telithromycin prevents bacteria from growing by interfering with their protein synthesis
.It binds to 50 s of the bacterial ribosome and blocks the progression of the growing
polypeptide chain.
• The telithromycin conventional tablets can be obtained as
300mg,400mg.Telithromycin can be easily absorbed and elimination is through
biliary, and renal route.Its half life40 is 10 hours.It is white in colour,odorless,it is
having good water solubility.its bioavalability is 57%.protein binding41 takes place
60-70% bound primarily to human serum albumin.These biopharmaceutical42 and
physicochemical properties reveal that telithromycin is the ideal candidate to develop
in to sustained action pellets.
Rationale for Drug Selection
1. Telithromycin is a highly water-soluble drug. It is Soluble in ethanol, methanol, DMF
or DMSO. Good water solubility.
2. The marketed sustained release formulations of Telithromycin are available in tablet
form. dosage of 300mg,400mg.In order to get sustained release pellets for easy drug
release.
3. Telithromycin has a biological half life 10 hours
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4. Adverse events associated with Telithromycin use are often gastrointestinal, including
diarrhea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also
occur. Less common side-effects include palpitations, blurred vision, and rashes.
Prolonged QTc intervals may also be caused by Telithromycin.These adverse effects may
be partially avoided during sustained release dosage form.
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3. REVIEW OF LITERATURE
DRUSANO.G43 et al
Telithromycin is a novel ketolide which is a semisynthetic derivative of erythromycin
A,having a 3-keto function instead of a 3-l-cladinose on the erythronolide A ring
.Telithromycin, a new ketolide antimicrobial agent, has sufficient potency, with an
antibacterial spectrum that covers all major respiratory tract pathogens, against isolates
from respiratory tract infections (RTIs) and exhibits potent antibacterial activity against
gram-positive aerobes, including Streptococcus pneumoniae, Streptococcus pyogenes,
fastidious gram-negative bacilli, including Heomophilus influenza and Moraxella
catarrhalis, intracellular pathogens, including Chlamydia pneumoniae, Legionella
pneumophila,and a typical mycophila as Mycoplasma .pneumonia.
CHOURASIA M.K JAIN44 et al
The purpose of designing multiparticulate dosage form is to develop a reliable
formulation that has all the advantages of a single unit formulations and yet devoid of the
danger of alteration in drug release profile and formulation behaviour due to unit to unit
variation ,change in gastro-luminal ph and enzyme population.
THANOO.B.C.SUNNY.45 et al
Pharmaceutical and research are increasingly focusing on delivery systems which
enhance desirable therapeutic objectives while minimizing side effects. Recent trends
indicate that multiparticulate drug delivery systems are especially suitable for achieving
sustained or delayed release oral formulations with low risk of dose dumping,flexibility
of blending to attain different release patterns as well as reproducible and short gastric
residence time.
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VANDEN MOOTER46 et al
For decades an acute disease or chronic illness is being clinically treated through delivery
of drugs to the patients in the form of some pharmaceutical dosage forms like tablets,
capsules, pills, creams, liquids, ointments, aerosols, injectables and suppositories.
Presently, these conventional dosage forms are primarily prescribed pharmaceutical
products and available over-the-counter. To achieve and maintain the concentration of an
administered drug within therapeutically effective range, it is often necessary to take drug
levels in plasma.
SINHA V.R KUMARIA47 et al
The goal of any drug delivery system is to provide a therapeutic amount of drug to the
proper site in the body to achieve promptly, and then maintain, the desired drug
concentration. That is, the drug delivery system should deliver drug at a rate dictated by
the needs of the body over the period of treatment. This idealized objective points to the
two aspects most important to drug delivery, namely, spatial placement and temporal
delivery of the drug. Spatial placement relates to targeting a drug to a specific organ or a
tissue, while temporal delivery refers to controlling the rate of drug delivery to the target
tissue. An appropriately designed sustained release drug delivery system can be a major
advance towards solving these two problems. It is for this reason that the science and
technology responsible for development of sustained release pharmaceuticals have been
and continue to be the focus of a great deal of attention in both industrial and academic
laboratories.
DEVEREUX J.E NEWTON48 et al
Sustained release systems include any drug delivery system that achieves slow release of
drug over an extended period of time. If the systems can provide some control,weather
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this be of a temporal or spatial nature, or both, of drug release in the body or in the other
words, the system is successful at maintaining constant drug levels in the target tissue or
cells,it is considered a controlled release system.
LIU ,L .FISHMAN49 et al
The design of sustained release delivery systems is subject to several variables of
considerable importance. Among these are the route of drug delivery, the type of delivery
system, the disease being treated, the patient, the length of therapy and the properties of
drug. Each of these variables is interrelated and this imposes certain constraints upon for
the route of delivery, the design of the delivery system and the length of therapy. Of
particular interest to the scientists designing the systems are the constraints imposed by
the properties of the drug. It is these properties, which have the greatest effect on the
behavior of the drug in the delivery system and in the body.
JOSEPH,N.J LAXMI50 et al
Drug stability : Of importance for oral dosage form is the loss of drug through acid
hydrolysis and / or metabolism in the GI tract. Most sustained release systems currently
in use release their contents over the entire length of GT tract. Thus, drugs with
significant stability problems in any particular area of the GT tract are less suitable for
formulation into sustained release systems that releases its contents throughout the GI
tract.
WADHWA .S51 et al
Given enormous advantages of multiparticulate systems over single-unit oral dosage
forms, extensive research has focused recently on refining and optimizing existing
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pelletization techniques as well as on the development of novel manufacturing
approaches that use innovative formulations and processing equipment.
SELLESIA.I.G52 et al
As sustained release systems, floating dosage forms offer various potential advantages
evident from several recent publications.Drugs that have poor bio availability because
their absorption is restricted to upper GI tract can be delivered efficiently thereby
maximizing their absorption and improving their absolute biavailabilities.
NS Dey, 53 et al
Pharmaceutical invention and research are increasingly focusing on delivery systems
which enhance desirable therapeutic objectives while minimising side effects. Recent
trends indicate that multiparticulate drug delivery systems are especially suitable for
achieving controlled or sustained release oral formulations with low risk of dose
dumping, flexibility of blending to attain different release patterns as well as reproducible
and short gastric residence time. The release of drug from microparticles depends on a
variety of factors including the carrier used to form the multiparticles and the amount of
drug contained in them. Consequently, multiparticulate drug delivery systems provide
tremendous opportunities for designing sustained release oral formulations, thus
extending the frontier of future pharmaceutical development.
CHIN J.E54 et al
The aim of this study was to examine the transport mechanism of telithromycin in
comparison with erythromycin, azithromycin, clarithromycin and roxithromycin.: These
antibiotics were examined in Caco-2 cell monolayers in order to demonstrate the
potential involvement of P-GP in the absorption process, using verapamil as a P-GP
competitor. A model using concentration equilibrium conditions was developed to
delineate passive and active permeability components of telithromycin and roxithromycin
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transport in order to predict absorption in humans. Comparison of telithromycin Papp
(AB)/Papp (BA) ratios with those of the other antibiotics indicated that an efflux pump
was involved which limited the transport of the macrolides to a greater extent than that of
telithromycin. Modulation of Caco-2 transport of these antibiotics by verapamil and their
reciprocal effect upon verapamil transport confirmed the involvement of P-GP and
demonstrated that two substrates of P-GP may increase the transport of each other.
Under concentration equilibrium conditions, both roxithromycin and telithromycin
exhibited high mean Papp values for passive diffusion which extrapolated to 88% and
77% predicted human absorption respectively, if the involvement of P-GP was
ignored.Both Km and Vm values suggested that saturation of P-GP by telithromycin may
occur at a lower dose level in humans than with roxithromycin (Km= 9.8µM, Vm= 0.3
µM and Km= 45 µM, Vm= 1.1 µM, respectively). At 4.10-5 M of either telithromycin or
roxithromycin the passive flux was respectively 48% and 16% greater than the active
efflux. The high absorption potential of telithromycin combined with the low Km and
Vm values and the high dose level suggest that in humans the efflux pump may not limit
ketolide absorption and that the interaction with other P-GP substrates may not
significantly increase its oral absorption.
RONINSON T.B55 et al
Telithromycin (HMR 3647) is a novel ketolide antimicrobial with good activity against
both common and atypical respiratory pathogens, including many resistant strains. This
randomized, three-period crossover study determined the dose proportionality of
telithromycin pharmacokinetics after single and multiple dosing in healthy subjects. In
each treatment period, subjects received a single oral dose of 400, 800 or 1,600 mg of
telithromycin followed 4 days later by the same dose once daily for 7 days. Blood and
urine samples were taken throughout the study for determination of pharmacokinetic
parameters for telithromycin and RU 76363, its main metabolite.
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INGUNN THO ET.AL 56 et al
It is studied low-soluble pectin derivative PA (degree of methoxylation,10%) as an
extrusion aiding excipient in pellet preparation by spheronisation /extrusion. The
substance has a high drug loading capacity and produces disintegrating pellets that are
well suited for fast delivery of drugs with a low water solubility. The pellets are also
mechanically stable, compared to MCC.
MARCEL DEKKER INC 57 et al
The concept of sustained release formulations was developed to eliminate the need for
multiple dosage regimens, particularly for those drugs requiring reasonably constant
blood levels over a long period of time. In addition, it also has been adopted for those
drugs that need to be administered in high doses, but where too rapid a release is likely to
cause undesirable side effects.
NEWTON JM 58 et alThe design of sustained release delivery systems is subject to several variables of
considerable importance. Among these are the route of drug delivery, the type of delivery
system, the disease being treated, the patient, the length of therapy and the properties of
drug. Each of these variables is interrelated and this imposes certain constraints upo
choices for the route of delivery, the design of the delivery system and the length of
therapy. Of particular interest to the scientists designing the systems are the constraints
imposed by the properties of the drug. It is these properties, which have the greatest
effect on the behavior of the drug in the delivery system and in the body.
AMIT KRISHNA RATNAKAR59 et al
The present invention provides a multiple unit compositions comprising of film coated
pellets and, wherein each pellet comprises: i) a core comprising active ingredient(s); ii)
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optionally a separating layer coated on the core; iii) at least two film layers comprising of
film polymers and plasticizer either coated on the core or on the separating layer to obtain
film coated pellets, such that the last film layer is formed from a solution comprising of
film polymer and plasticizer in organic solvent(s), resulting in no appreciable change in
release profile of active ingredient.
T Karunakar Reddy60 et al
The objective of the present study is to focus on formulation of Telithromycin film
coated pellets by Wurster coating technique with fluid bed processor, in the form of
capsules,). In this formulation film formers like Povidone and HPMC are used in drug
loading stage and Talc is used in film coated stage in the formulation of telithromycin
coated pellets.
S.THIERRY61 et al
The drug loaded core pellets were produced by aqueous extrusion
spheronization technique using microcrystalline cellulose as a spheronizing aid and PVP
K 30 as a binder. Different coat weights of Eudragit S-100 were applied to the drug
loaded pellets in an automatic coating machine to produce the pH sensitive coated pellets.
In vitro dissolution studies of the coated pellets performed following pH progression
method showed that the drug release from the coated pellets depended on the coat
weights applied and pH of the dissolution media.
D.Kumaraswamy62 et al
A new simple, rapid and reliable UV Spectrophotometry method was developed and
validated for the estimation of Telithromycinin blend & Capsules formulations. The
method was based on simple UV estimation in cost effective manner for regular
laboratory analysis. The instrument used was Perkin Elmer, UV Spectrophotometer
(Lambda 25) and using 0.1 N NaoH as solvent system. Sample were analysed using UV
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Win Lab 5.2.0 Software and matched quartz cells 1 cm and was monitored at 302 nm.
Linearity was obtained in the concentration range of 2 - 10 mg mL–1 for telithromycin
The validation parameters, tested in accordance with the requirements of ICH guidelines,
prove the suitability of this method.
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4. METHODOLOGY
LIST OF EXCIPIENTS AND MATERIALS.
Name of Excipient Manufacturer/supplier.
Telithromycin HEFEI TNJ CHEMICAL INDUSTRY
Sugar: Dynamix dairy industries Sodium CMC : Hercules aqualon Maize starch : Maize products Potato starch : Avebe
Pregelatinised starch : Avebe Colloidal anhydrous silica: Intas Pharma Titanium dioxide : Kronos international Magnesium stearate : Amshi drugs Non pareil seeds: Homedicines
Talc : Ashok minerals
crasmellose : Triveni inter chem.pvt.ltd
Hypermellose: shaanxi top pharm chemical co ltd
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LIST OF EQUIPMENTS USED
Name of the equipment Make
Extruder and spheronizer Modern plastic and equipments
Hplc Agilent Technologies
Fluidized bed dryer Neelam industries
Tap density testor Electro lab
Uv visible spectrometer Shimadzu
Friability tester Electro lab
Dissolution testor Electro lab
Bulk density Electronics India
Stability chamber Thermo lab
Mechanical stirrers Remi motors
Weighing balance 5kg Mettler toledo
Weighing balance 10 kg Mettler toledo
Digital balance Mettler toledo
Ph meter Mettler toledo
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Marketed MUPS sustained release pellets formulation
Company Drug Therapeutic Category formulation type
Elilily Erythromycin Antibiotic sustained release
Triveni chemicals diclofenac NSAID sustained release
Ssamex overseas ketorolac NSAID sustained release
Hainan coltd fenofibrate statin sustained release
Shanghai pharma theophyllone asthma sustained release
IDEAL CHARACTERISTICS OF EXCIPIENTS
1.Drug should be water soluble to perform the formulations.
2.Polymer should have compatibility with drug and other excipients.
3.It should have good coating agent.
4.Filler should have good capacity to fill and compatible with other excipients.
5.Binding agent should also have good binding agent to bind the substances very well.
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6.Disintegrant agent should soluble in other excipients and should compatible with other
excipients.
DRUG-EXCIPIENT COMPATIBILITY
1.We have selected some excipients based on above characteristics
They are
A –Chemical nature
B- Impurity profile
C- Physical form
D- Moisture content
E-Surface area
F-Particle size
G-Morphology.
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• EXCIPIENTS DETAILS
• Details of Non-Pareil Seeds
Non proprietary names Sugar spheres
Synonyms Non-pareil; Non-pareil 103;Nonpareilseeds; Nu-core; Nu-pareil;sugar seeds
Functional category Tablet and capsule diluents
Applications Used as inert cores in capsules andtablets formulations particularlyfor sustained release dosage forms
Description Spherical granules of a labelednominal –size range with uniformdiameter and containing not lessthan 62.5 % and not more than91.5 % sucrose
Typical properties Solubility in water variesaccording to the sucrose to starchratio. The sucrose component isfreely soluble in water whereas thestarch component in soluble incold water.
Stability and storage Stable when stored in cool anddried place in a well closedcontainer
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Method of manufacture Made up from crystalline sucrose, which is coated using sugar syrupand a starch – dusting powder.
Details of sugar
Non proprietary names Compressible Sugar
Synonyms Direct compacting sucrose: Nu TAB
Emperical formula Contains, not less than 95.0 % and
not more than 98.0 % of sucrose
Functional category Tablet and capsule diluents, sweetening agent
Applications Dry binder in tablet formulationFiller in chewable tabletsSweetener in chewable tablets
Description Sweet – tasting, white crystallinepowder.
Typical properties Bulk density: 0. 492 g/cm3Tap density: 0.6 g/cm3Moisture content: 0.57%
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Stability and storage : Stable in air under normalconditions of room temperature. Should be stored in well-closedcontainer in a cool, dry place.
Method of manufacture It is prepared by cocrystalization ofsucrose
Details of talc
Non proprietary names Purified talc, talc, talcum
Synonyms 553b;magsil osmanthus; magsil
star; powdered talc
Empirical formula It is purified, hydrated,magnesium
silicate
Functional category Anti sticking agent; glidant; tablet
and capsule diluent and lubricant
Applications Dusting powder preparationTablet and capsule glidant and
lubricant
Description Fine, white to grayish-whitecolored, odour less , impalpable,
unctuous, crystalline powder
Method of manufacture It is naturally occurring
hydropolysilicate mineral
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Details of titanium dioxide
Non proprietary names Titanium dioxide; titanium oxide;titanii dioxidum.
Synonyms Anatase titanium dioxide; kowett;kronos
Empirical formula Tio2
Functional category Coating agent and pigment
Applications It is widely used in confectionery, cosmetics, foods and topicalpreparations
Description White, amorphous, odorless, andtasteless non-hygroscopic powder.
Typical properties Bulk density: 0.4-0.62 g/cm3Tap density: 0.625-0.830 g/cm3
Stability and storage Stable material at high temp.itshould be stored in well-closedcontainer in a cool and dried place.
Method of manufacture It is naturally occurring mineralrutile, Anatase and brookite.
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Details of magnesium stearate
Non proprietary names Magnesium stearate, magnesiistearas.
Synonyms Magnesium octadecanoate
Empirical formula C36H70MgO4
Structural formula (CH3 (CH2) COO) 2Mg
Functional category Tablet and capsule lubricant
Applications It is widely used in cosmetics, foods and topical preparations
Description Fine, white, precipitated or milled, impalpable powder of low bulkdensity.
Typical properties Bulk density: 0.159 g/cm3Tap density: 0.286 g/cm3Flash point: 250º C
Stability and storage
conditions
It is stable and should be stored ina well-closed container in a cool, dry place
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DETAILS OF SODIUM CMC
Non proprietary names Carmellose
Synonyms Akucell; aquasorb; blanose; cekol
Empirical formula It is sodium salt of apolycarboxymethyl ether ofcellulose.
Functional category Coating agent, binder,disintigrantApplications It is used in oral and topical
formulations as emulsifying agent,gel-forming agent.
Description White to almost white colored, odorless, granular powder.
Typical properties Bulk density: 0.520 g/cm3Tap density: 0.783 g/cm3melting point: 227º C
Stability and storageconditions
It is stable though hygroscopicmaterial. Under high humidityconditions it can absorb largequantity of water. It should bestored in a well-closed container ina cool, dry place.
Method of manufacture It is prepared by steeping cellulose.
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Details of starch
Non proprietary names Maize starch, potato starch
Synonyms Amido; amidon; amilo
Empirical formula (C6H10O5)n
Functional category : Glidant, binder in both tablets andcapsules.
Applications It is used in oral solid dosageforms, topical dosage forms
Description White colored, odorless, tastelesspowder.
Typical properties Bulk density: 0.462 g/cm3Tap density: 0.658 g/cm3
Stability and storage Dry, unheated starch is stable ifprotected from high humidity. It should be stored in an airtightcontained in a cool, dry, place.
Method ofManufacturing
It is extracted from plant sourcesthrough a sequence of processingsteps involving coarse milling, repeated water washing, wetsieving, and centrifugal separation
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Details of pregelatinized starch
Non proprietary names starch, pregelatinised starch
Synonyms Instastarch; lycatb PGS
Empirical formula (C6H10O5)n
Functional category Glidant, binder in both tablets andcapsules.
Applications It is used in oral solid dosageforms, topical dosage forms
Description : White colored, odorless, tastelesspowder.
Typical properties Bulk density: 0.586 g/cm3Tap density: 0.879 g/cm3
Stability and storage Dry, unheated starch is stable ifprotected from high humidity. It should be stored in an airtightcontained in a cool, dry, place
Method ofManufacturing
It is prepared by heating aqueousslurry containing up to 42 % w/wof starch at 62-72 º C 32.
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Details of hypermellose
Non proprietary names Hydroxypropyl methylcellulose;hydroxypropyl methyl cellulose;HPMC; E464
Synonyms E1440 ,hydroxylpropyl starch
Empirical formula OCH2CHOHCH3binding agent; disintegrant;emulsifying agent; thickeningagent;viscosity-increasing agent.Itis used in antiseptics and is usedwidely in cosmetics. It is also usedanalytically as a bioseperationaqueous phase forming polymerfree-flowing white to off-whitecoarse powder.Acidity/alkanity ph4.5-5.7(10%w/v aqueous dispersionsolubility practically insoluble inwater and ethanol 95%ether. Hydroxypropyl starch is stable athigh humidity and is consideredtobe inert under normal conditions. Itis stable in emulsion system. Hydroxypropyl starch is producedindustrially from naturalstarch,using propylene oxide asthe modifying reagent in thepresence of alkali addinghydroxyl propyl groups at theOH positions by an etherlinkage
Functional categoryApplications
Description
Typical properties
Stability and storage
Method ofManufacturing
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1 PREFORMULATION STUDIES
Preformulation involves the application of biopharmaceutical principles to the
physicochemical parameters of drug substance are characterized with the goal of
designing optimum drug delivery system.
Before beginning the formal preformulation the following factors to be
considered,
The amount of drug available.
The physicochemical properties of the drug already known.
Therapeutic category and anticipated dose of compound.
Pre formulation may be described as a phase of the research and development process
where the formulation scientist characterizes the physical, chemical and mechanical
properties of a new drug substance, in order to develop stable, safe and effective dosage
forms. Ideally, the Pre formulation phase begins early in the discovery process such that
appropriate physical, chemical data is available to aid in the selection of new chemical
entities that enter the development process. During this evaluation possible interaction
with various inert ingredients intended for use in final dosage form are also considered
2 Drug-Excipient compatibility studies:
Drug excipient compatibility studies were carried out by mixing the drug with various
excipients in different proportions (in 1:1, 1:0.5 ratio were prepared to have maximum
likelihood interaction between them) was placed in a vial, and rubber stopper was placed
on the vial and sealed properly. Studies were carried out in glass vials at Accelerated
conditions, 40ºC ± 2°C / 75%RH ± 5 % RH and a storage period of 4 weeks. After
storage, the sample was compared with control at 2-8°C and observed physically for
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liquefaction, caking, and, discoloration. The compatibility study was also carried out by
differential scanning calorimetric (DSC) analysis
SNO Excipient Ratio code
1 PURE API 1 A
2 PURE API+HPMC 1:1 B
3 PURE API+SODIUM
CMC
1:2 C
4 PURE API +TALC 1:3 D
5 PURE API+SODIUM
CMC
1:1 E
6 PURE
API+HYPERMELLOSE
1:0.5 F
7 PURE API+MAGNESIUM
STEARATE
0.5:1 G
8 PURE API+COLLOIDAL
SILICATE
1:2 H
9 PURE
API+TRIETHYLCITRATE
1:1 I
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Experimental MethodsPreparation of Buffers and Reagents
Sodium hydroxide solution, 0.2 M: 8.0 g of sodium hydroxide was dissolved in
distilled water and diluted to1000 ml with distilled water.
Potassium dihydrogen phosphate solution, 0.2 M: 27.218 g of potassium dihydrogen
phosphate was dissolved in distilled water and diluted to 1000 ml.
Hydrochloric acid solution, 0.1 N: 8.5 ml of concentrated hydrochloric acid was diluted
with distilled water and volume was made up to 1000 ml with distilled water. pH (1.2)
was adjusted with dilute hydrochloric acid.
Phosphate buffer solution, pH 6.8: 250 ml of 0.2 M potassium dihydrogen phosphate
was placed in a 1000 ml volumetric flask, 112 ml of 0.2 M sodium hydroxide was added
and then volume was adjusted with distilled water up to 1000 ml. pH was adjusted to 6.8
with dilute sodium hydroxide.
Analytical Methods
Preparation of Telithromycin standard Stock solution in phosphate buffer
solution, pH7.5: A standard stock solution of Telithromycin was prepared by dissolving
accurately weighed 100 mg of Telithromycin with little quantity of phosphate buffer
solution, pH 7.5in a 100 ml volumetric flask .The volume was made up to 100 ml with
phosphate buffer solution, ph 7.5to obtain a stock solution of 1000μg/ml.
Determination of analytical wavelength: From the standard stock solution, 1 ml was
pippeted into 100 ml volumetric flask. The volume was made up to 100 ml with
phosphate buffer solution, pH 7.5The resulting solution containing 10 μg/ml was scanned
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 51
between 200 and 400 nm. The λmax was found to be 263 nm. It is represented in the
below
Calibration curve of Telithromycin in phosphate buffer pH7.5:
Accurately weighed quantity of Telithromycin (100 mg) was dissolved in little quantity
of phosphate buffer solution, pH7.5, and volume was made up to 100 ml. From this, 1 ml
of solution was pippeted out in to a volumetric flask and volume was made up to 100 ml.
Appropriate aliquots were taken into different volumetric flasks and volume was made up
to 10 ml with phosphate buffer solution, pH7.5, so as to get drug concentrations of 4 to
24 g/ml. The absorbencies of these drug solutions were estimated at max 263 nm.
This procedure was performed in triplicate to validate the calibration curve. The data
were given in Table 11. A calibration curve was constructed as shown in the figure.
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 52
Data for Standard Plot of Telithromycin in Phosphate Buffer Solution, pH 7.5
1.2
1.0
0.8
0.6
0.4
0.2
0 4 8 12 14 16 20 22 24
SR. No.Concentration( g/ ml)
Absorbance at263nmnmAM + SD
1 0 0.00 + 0.000
2 4 0.16 + 0.001
3 8 0.33 + 0.003
4 12 0.48 + 0.002
5 16 0.58 + 0.002
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 53
Concentration in mcg/ml
Calibration curve of Telithromycin in phosphate buffer solution, pH7.5, at 263nm.
Interference of additives: Each additive weighing 10 mg was placed separately in a
series of 50 ml volumetric flasks containing 10 g/ml drug solutions in phosphate buffer
solution pH, 6.8. The flasks were kept aside for 45 minutes with occasional shaking. The
solutions were filtered and the absorbances of these solutions were measured at 226 nm
against blank reference. The absorbances of these solutions wer compared with the
absorbance of drug solutions without any additive.
Absorbances of Solution Containing Excipients With Drug And Without Drug At
263 Nm In Phosphate Buffer Solution, pH.7.5
DOSAGE FORM ANALYSIS BY HPLC METHOD
Solution Drug ProductPlacebo
Range
Interference
Yes / no
Absorbance 0.449 0.443 0.001-
0.004
No
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 54
Chromatographic condition
Stationary phase hypersil
Mobile phase buffer
Sph 7.4with koh solution
Flow rate 1ml/min
Control temperature ambient
Detector 280nm
Injection volume 20 microlitres.
Preparation of buffer
Dissolve 2.72g of kH2P04&0.525g of k2HPO4 and volume
makeup up to 1000 ml of purified water
PREPARATION OF STANDARD
1.40.4 mg of drug dissolved in 20 ml of methanol from this 2ml of solution dilute
2. And volume makes up to 50 ml with mobile phase.preparation of sample 40mg of
drug equivalent to 20ml of volumetric flask then add 15ml methanol and Sonicate it
passed through micrometer filter take 2ml of filtrate add volume up to 50 ml.
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 56
Angle of repose: The angle of repose of Telithromycin pellets was determined by the
funnel method (Reposogram). The accurately weighed quantity of pellets was taken in a
funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just
touches the apex of the heap of the pellets. The pellets were allowed to flow through the
funnel freely onto the surface. The diameter of the powder cone was measured and angle
of repose was calculated using the following equation.
tan = h/r (16)
Where h and r are the height and radius of the pellets cone, respectively. Flow
properties for different values of angle of repose were given below
Comparison Between Angle of Repose and Flow Property of Pellets or Drug
Angle of Repose Flow property
<25 Very bad
25-30 average
30-40 excellent
Bulk density: Loose bulk density (LBD) and tapped bulk density (TBD) were
determined. Telithromycin was passed through a #18 sieve to break the clumps, if any.
Accurately weighed 50 g of the drug was placed in a 100 ml graduated measuring
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 57
cylinder. Initial volume was observed. The cylinder was tapped initially 500 times from a
distance of 14 + 2 mm. The tapped volume (Va) was measured to the nearest graduated
unit. The tapping was repeated additional 750 times. Again the tapped volume was
measured to the nearest graduated unit. The LBD and TBD were calculate in g per ml
using following formulae
LBD = weight of the powder/volume of the packing (17)
TBD = weight of the powder/tapped volume of the packing
Particle size distribution: This practice was done for the pellets obtained after drug
coating to check average size of the pellets. 100 gms of the pellets were shifted in to sieve
shaker, the machine was run for 5 minutes, all the sieves were taken out and collected
the retained pellets by respective sieve and the % retention of pellets by that sieve was
calculated.
FORMULATION DEVELOPMENT
Telithromycin Sustained action Pellets: In this work, the method used for
preparing telithromycin sustained action pellets was extrusion-spheronising
technique
Extrusion-spheronising technique
The three main steps followed in Extrusion-spheronising technique to prepare sustained
release pellets of Telithromycin
1.GRANULATION:
2. COATING
3. PREPARATION OF PELLETS
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 58
1. At first granulation is done and later coating takes place finally pellets are prepared
2. At first it should pass through mesh size of 30# and it should passed through
Extruder 40rpm.
3. Later by subcoating with wurster intial with opadry clear 4%build up)
4. Later it is sifted material to rapid mixer granulater and spheronization is done at
800 rpm and polymer coating takes place
5.And allowed it for dry mixing for 10 minutes and rpm speed is 150 rpm .1800rpm
For 30 sec 1300rpm for 60 sec.
6 .Water is added for 3minutes till the formation of granules
7 .The chopper runs for 3 minutes for 1000rpm to complete granulation process
The size is 16/30 mesh
8. Finally pellets are formed
9. Allow these pellets for fluidized bed dryer for few minutes
10. By maintaining the temperature
11. After preparation of pellets we have to study the pellets by using different
excipients to get sustained action.
12. By this we can able to know which excipient is suitable for sustained action
Prototype Formulation
After studying the patents on telithromycin sustained release pellets, a list of binders,
which can be used, was prepared which included various binders like sugar,sodium
CMC, maize starch, potato starch, and Pregelatinised starch. Feasibility trial was
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 59
performed in order to bind the drug on to the non-pareil seeds using these binders. The
first binder selected was sugar and in total four trials were taken using sugar as binder.
For all the trials the coating solution was prepared by the following method:
Preparation of Coating Solution for batches 1 to 4.
Steps:1. Sugar was dissolved in water.
2. Telithromycin was dissolved in sugar solution
3. Talc was added to the above solution.
4. A white milky solution was obtained, which was then passed through # 30sieve
Formulation of Telithromycin For 100 Capsules.
Ingredients no Formulation Ingredients No.
1 2 3 4
Non pareil seeds 21.3 21.4 21.4 21.4
Telithromycin 4.1 4.1 4.1 4.1
Sugar 1.06 1.62 1.62 1.62
Talc 1.22 1.23 1.22 1.22
Purified water 10 10 10 10
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 60
Composition of Telithromycin pellets
Ingredient F
1
F
2
F
3
F
4
F
5
F
6
F
7
F
8
F
9
F
10
F
11
Core spheroids
Telithromy
cin)
. 1
69.7
1
69.7
1
69.7
1
69.7
1
69.7
. 1
69.7
1
69.7
1.
69.7
. 1
69.7
1
69.7
1
69.7
.
MCC (PH
101)
1
65.3
1
34.3
1
34.3
1
34.3
1
34.3
1
34.3
1
65.3
1
65.3
1
34.3
1
65.3
1
65.3
Lactose(Gran
ular 200)
1
00
5
5
5
5
5
5
7
5
1
00
1
00
7
5
5
5
5
0
7
5
HPC(Klucel
EXF)
1
0
6 1
0
6 1
0
1
0
6 1 6 6 1
0
Water QS
Total core
spheroids
4
45
3
65
3
69
3
65
3
89
4
14
4
41
3
91
3
65
3
91
4
20
Sub coat
HPMC 6 cps 1
4
1
0.5
1
0.5
1
0.5
1
0.5
1
0.5
1
4
1
0.5
1
0.5
1
4.5
1
5.5
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 61
Talc 6 4
.5
4
.5
4
.5
4
.5
4
.5
4
.5
6 4
.5
6 6
Total sub
coat spheroids
4
65
3
80
3
84
3
80.0
4
04
4
29
4
59.5
4
07.5
3
80
4
11.5
4
41.5
EC coating
Ethyl
cellulose 20 cps
5
6
4
5
4
5
6
6.6
5
6
6
6.6
7
5
7
5
5
6.2
7
5
7
5
CHARACTERIZATION OF THE FORMULATION
Precompression parameters
A) Characterization pellets, extra granular blend
1. Bulk density:
Bulk density of a compound varies substantially with the method of crystallization,
milling or formulation. Bulk density is determined by pouring pre sieved granules into a
graduated cylinder via a large funnel and measure the volume and weight.
Bulk density = weight of granules
2. Tapped density
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V. Mridula, Dept. of Pharmaceutics Page 62
Tapped density is determined by placing a graduated cylinder containing a
known mass of granules and mechanical tapper apparatus, which is operated for a fixed
number of taps until the powder bed volume has reached a minimum volume. using the
weight of the drug in the cylinder and this minimum volume, the tapped density may be
computed.
Tapped density = weight of granules
Tapped volume of granules
Determination of Bulk & tap Density: An accurately weighed quantity of the powder
(W), was carefully poured into the graduated cylinder and the volume (Vo) was
measured, then the graduated cylinder was closed with lid, set into the density
determination apparatus.
The bulk density, and tapped density were calculated using the following Formulas
Bulk density = W / Vo
Tapped density = W / Vf
Where,
W = weight of the powder
Vo = bulk volume
Vf = tapped volume
3. Compressibility Index:
Carr’s Index is measured using the values of bulk density and tapped density. The
following equation is used to find the Carr’s index.
CI = (TD-BD) x100
Tapped density
Where TD = Tapped density
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 63
BD = Bulk density
4. Hausner’s Ratio:
It indicates the flow properties of the powder and ratio of Tapped density to the
Bulk density of the powder or granules. (Values are given in Table No:5)
Hausner’s Ratio = Tapped density/Bulk density
Scale of Flowability
Compressibility
Index
Flow Character Hausner Ratio
10 Excellent 1.00-1.11
11-15 good 1.13-1.18
16-20 Fair 1.19-1.25
21-25 passable 1.20-1.25
26-31 poor 1.35-1.45
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 64
Post compression parameters
1. Physical appearance:
The general appearance of tablets, its visual identity and overall elegance is
essential for consumer acceptance. The control of general appearance of tablet involves
measurement of number of attributes such as tablet size, shape, color, presence or
absence of odor, taste, surface texture and consistency of any identification marks.
2. Hardness:
The resistance of tablets to breakage, under conditions of storage, transportation or
handling before usage depends on its hardness. The hardness of tablet of each
formulation was checked by using Dr.Schleuniger Hardness tester in terms of Kilo ponds
(KP).
3. Thickness:
Thickness of tablet is important for uniformity of tablet size. Thickness was measured
using Vernier caliper. It was determined by checking ten tablets from each formulation.
4. Friability:
This test is performed to evaluate the ability of tablets to withstand abrasion in packing,
handling and transporting. Initial weight of 20 tablets is taken and these are placed in the
friabilator, rotating at 25rpm for 4min. The difference in the weight is noted and
expressed as percentage. It should be preferably between 0.5 to 1.0%.
%friability = (W1-W2)/W1 X 100
31-34 Very poor 1.47-1.59
> 38 Very very poor > 1.60
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V. Mridula, Dept. of Pharmaceutics Page 65
Where, W1= weight o f tablets before test
W2 = weight of tablets after test
5. Estimation of drug content:
Ten pellets from each formulation were powdered. The powdered sample equivalent to
56 mg of drug was transferred to a volumetric flask. Required amount of 0.1 M NaoH
was added, mixed and filtered, the filtrate was suitably diluted with 0.1 M NaoH and
analyzed against blank by UV spectrophotometer at 305nm (shiatsu UV-1700)
6. Acid resistance by physical observation:
Preparation of 0.1N HCl:
Dilute 85.6 ml of concentrated HCl in 10 liters of water and mix well.
Procedure: Transfer 900 ml of dissolution medium into dissolution vessel. Transfer one
tablet into each of vessel and fix the paddle, lift down the instrument and run
immediately. The temperature should be 37+0.5. After 2 hr time interval observe the
color change in media (yellowish green) and the color change in pellets (brownish color),
withdraw pellets from each vessel. The samples were analyzed by assay procedure at
305nm using double beam UV-Visible spectrophotometer. The content of drug (%
release in acid) was calculated using equation generated from standard calibration curve.
7. Dissolution (By UV):
Dissolution is a process by which the disintegrated solid solute enters the solution. The
test determines the time required for a definite percentage of the drug in a tablet to
dissolve under specified conditions.
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 66
Dissolution Parameters
Medium : 7.5 phosphate buffer
Apparatus : paddle (USP-1I)
RPM : 100
Temperature : 37o C
Time Points : 5, 10, 15, 30, 45, 60 min.
Buffer stage by UV:
For the oral dosage forms the in vitro dissolution study must be conducted in the
dissolution medium which simulate the in-vivo conditions (actual physiological
conditions).. The in vitro drug release studies from the prepared formulation were
conducted for a period of 1 hr using an Electro lab model dissolution tester USP Type-2
apparatus (rotating paddle) set at 100 rpm and a temperature of 37± 0.5°C.formulation
was placed in the 900ml of the medium. At specified intervals 5ml samples were
withdrawn from the dissolution medium and replaced with fresh medium to keep the
volume constant. Further dilutions of the sample was done(5ml to 10ml)with the
dissolution media of 7.5 buffer
The sample solution was analyzed at 305 nm for the presence of Model Drug, Using a
UV-visible spectrophotometer. It was justified that none of the ingredients used in the
formulation interfered with the assay method.
In vitro drug release kinetic studies
Kinetic model had described drug dissolution from solid dosage form where the dissolved
amount of drug is a function of test time. In order to study the exact mechanism of drug
release from the pellets, drug release data was analyzed according to zero order, first
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V. Mridula, Dept. of Pharmaceutics Page 67
order, Higuchi square root, Korsmeyer- Pappas model. The criteria for selecting the most
appropriate model were chosen on the basis of goodness of fit test.
The order and mechanism of Drug release from the dosage form were determined
by fitting the release rate studies data into Equations 1, 2, and 3. The values of K, KH, Ko,
n,t50% (time required for 50% of drug release), and r (correlation coefficient) were
determined. based on the value of n obtained by fitting the data into Equation 3, we
can describe the mechanism of drug release from the formulation.
Mt/M =Kot………….(1)
Mt/M =KHt1/2………….. (2)
Mt/M =Ktn……………… (3)
Where Mt/M is the fraction of drug released at any time t; and Ko, KH, and K are release
rate constants for Equations1, 2, and 3, respectively. In Equation 1, n is the diffusional
exponent indicative of mechanism of drug release. Nature of release of the drug from the
designed DR reservoir pellets and matrix pellets was inferred based on the correlation
coefficients obtained from the plots of the kinetic models. The data were processed for
regression analysis using MS EXCEL
Accelerated Stability study of the optimized batch
In order to determine the change in evaluation parameters and in vitro release profile on
storage, stability study of optimized batch was carried out at accelerated storage
condition at temperature 40 ± 20 C and 75% ± 5% RH in a humidity chamber for 1
month. Sample were withdrawn after 30 days interval and evaluated for change in in-
vitro drug release pattern, physical appearance.
Differential scanning calorimetric (DSC) analysis:
The physicochemical compatibilities of the Optimized formulations were tested by
differential scanning calorimetric (DSC) analysis. DSC thermograms of the powdered
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 68
tablets were derived from a DSC with a thermal analysis data station system, computer,
and plotter interface. The instrument was calibrated with an indium standard. The
samples (2-4 mg) were heated (50°C-300°C).
X-Ray Diffraction studies:
Crystallinity of the drug and the samples was determined using the Philips Analytical
XRD (Model: PW 3710, Holland) with copper target. The conditions were: 40 kV
voltages; 30 mA current; at room temperature. The samples were loaded on to the diffract
meter and scanned over a range of 2_Theta values form 30 to 600 at a scan rate of 0.05 0
/min
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 69
5. RESULTS
Sustained release pellets were developed for Telithromycin with a view to deliver the
drug in
a sustained manner. The details of results and discussion were given in the following
sections.
PREFORMULATION STUDIES
Description White colour
solubility
solubility-soluble in Ethanol,Methanol
it is good water solubility
Flow properties of API
Test Result
Bulk density 0.545
Tapped density 0.675
Cars index 19.26
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 70
Hausner’s ratio 1.23
Particle size distribution:
SieveNo.
Nominal meshaperture size,
m
Aperturesize(passed/Retained),
m
Meansizeopeningd, m
Weightofpowderundersize
%weightretainedonsmallersieve n,
m
Weightsizen x d
pan - - - - - -
16 1000 1000/pan 1000 0 0 0
20 710 710/1000 855 1 1 855
25 600 600/710 655 7 7 4585
30500 500/600
55089.5 89.5
49225
(n) =
100
(nd) =
54665
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 71
Drug-Excipient compatibility study at 40°C/75% RH
After 4 Weeks of study physical appearance of these compositions were compared with
the initial observations. The observations were recorded in the following.
Visual observation for Drug- Excipient Compatibility Study
Composition
Code
Initial I Week
40°C/75%
RH
II Weeks,
40°C/75%
RH
III Weeks,
40°C/75%
RH
IV Weeks,
40°C/75%
RH
AWhite
color fine
powder
White color
fine powder
White color
fine powder
White
color fine
powder
White
color fine
powder
B greyWhite
colored
powder
greyWhite
colored
powder
greyWhite
colored
powder
greyWhite
colored
powder
greyWhite
colored
powder
CWhite
colored
powder
White
colored
powder
White
colored
powder
White
colored
powder
White
colored
powder
D Blackcolored
solid
Blackcolored
solid
Black coloredSolid
Blackcolored
solid
Blackcolored
solid
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 72
EBlack
coloredsolid
Blackcolored
solid Black coloredsolid
Black
colored
solid
Black
colored
solid
FYellow
coloured
semi solid
Yellow
coloured
semi solid
Yellow
coloured semi
solid
Yellow
coloured
semi solid
Yellow
coloured
semi solid
G White
colored
powder
White
colored
powder
White colored
powder
White
colored
powder
White
colored
powder
H Pinkish
white
colored
Pinkish
white
colored
Pinkish white
colored
Pinkish
white
colored
Pinkish
white
colored
I Yellowish
colored
semisolid
Yellowish
colored
semisolid
Yellowish
colored
semisolid
Yellowish
colored
semisolid
Yellowish
colored
semisolid
J White
colored
powder
White
colored
powder
White colored
powder
White
colored
powder
White
colored
powder
k White colored powder
White colored powder
White colored
powder
White colored powder
White colored powder
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 73
After the storage, the samples were observed physically for discoloration. Physical
mixture of drug with pellets excipients after storage period of 4 weeks at 40°C / 75% RH
showed no physical changes. Hence the selected excipients were likely to be suitable for
the preparation of the pellets
Differential scanning calorimetric (DSC) analysis
The DSC thermo grams of Pure drug and other physical mixtures of various excipients
were as shown in figures. Various parameters like peak onset, peak and peak end set were
summarized in Table.
Diffrential scanning calorimetric studies
A-PELLETS
B-Telithromycin +HPMC
V. Mridula, Dept. of Pharmaceu
C-Telithromycin +sodium cmc
D-PURE DRUG TELITHROM
Telithrom
utics
c
MYCIN
mycin Pellets
Page 74
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 75
Evaluation of Pellets
Bulk
density
Tapped
density
carrs index hausners ratio
0.63 0.66 14.24 1.16
0.68 0.69 12.89 1.13
0.64 0.59 11.21 1.15
0.59 0.64 10.23 1.14
0.66 0.63 9.08 1.23
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 76
IN VITRO RELEASE PROFILE OF TELITHROMYCIN
% Drug release in 7.5PH phosphate buffer
A
F1
B
F2
C
F3
D
F4
F
F5
GF6
10.41.2 37.13
69.1239.5
48.6
20 42.87 44.12 76.9 49.5 56.9
30 52.12 56.289.12
58.4 67.9
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70
Time(min)
%Drugrelease B1
F1
F2
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70
Time(min)
%Drugrelease
F1
F2
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 77
45 60.06 60.4 90.59 64.2 78.6
60 73.09 65.3 92.8 70.54 87.3
70 80.3 64.3 80.3 70.3 60.3
x-ray diffraction
X-ray Diffraction studies were performed for proton pump inhibitor and optimized
formulations at various storage conditions (Initial, Accelerated stability-40 ± 2˚C/75 ±
5% RH).
V. Mridula, Dept. of Pharmaceu
Standard calibration curve o
Sr.No)*Conc.(
0
1
1
Telithrom
utics
of Telithromycin in 0.1 HCL
(mg/ml) Absorbance (nm)*
0 0
100.145±0.056
mycin Pellets
Page 78
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 79
2
20
0.280±0.075
3
30
0.427±0.064
4 40 0.576±0.062
5 50 5 50 0.695± 0.045
Each value represents mean ± S.D. (n = 3)
Cali ration curve of Telithromycin in 0.1 N HCl
y = 0 . 0 1 4 x + 0 . 0 0 2 8
R 2 = 0 . 9 9 9 2
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 80
absorbance
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 10 conc 20 30 40 50 60
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 81
I n - V i t r o D i s s o l u t i o n s t u d y
80
70
60
50
40
30
20
10
0
Time
0 10 20 30 40 50
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 82
Scanning electron microscope
Scanning Electron Photographs of different batches.
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 83
E1 E2 E3 E4 FL1 FL2 FL3 FL4 FD1 FD2 FD3
Circularity
S.D
0.832
0.06
7
0.790
0.04
5
0.800
0.05
2
0.800±0.05
2
0.821
0.05
3
0.821
0.05
3
0.804
0.07
2
0.794
0.07
8
0.891
0.04
1
0.923
0.03
5
0.936
0.06
3
Elongation
S.D
1.250
0.09
1
1.391
0.09
7
1.341
0.08
9
1.406
0.09
8
1.259
0.09
8
1.293
0.08
3
1.316
0.09
6
1.346
0.08
9
1.161
0.09
4
1.110
0.06
8
1.056
0.08
9
Rectang
S.D
0.830
0.05
7
0.836
0.06
8
0.831
0.06
5
0.837
0.06
3
0.833
0.07
1
0.836
0.05
9
0.836
0.05
9
0.841
0.07
2
0.799
0.06
3
0.789
0.05
8
0.791
0.06
4
Telithromycin Pellets
V. Mridula, Dept. of Pharmaceutics Page 84
6. DISCUSSIONS
Telithromycin , is a practically more soluble in water . Telithromycin prevents
bacteria from growing, by interfering with their protein synthesis. Telithromycin binds to
the subunit 50S of the bacterial ribosome, and blocks the progression of the growing
polypeptide chain. Telithromycin has over 10 times higher affinity to the subunit 50S
than erythromycin. In addition, telithromycin strongly bind simultaneously to two
domains of 23S RNA of the 50 S ribosomal subunit, where older macrolides bind
strongly only to one domain and weakly to the second domain. Telithromycin can also
inhibit the formation of ribosomal subunits 50S and 30S.
Telithromycin can metabolize through liver.Its half life is 10 hrs.Telithromycin
sustained action pellets can be performed by various techniques.
Among them extrusion spheronizer technique is new technique now a days.and
shows results accurately.we have to use many binders and coating agents to show the
sustained action
We had performed many evaluation parameters.
Bulk density
Tapped density
Porosity
Carrs index
Angle of repose.
Telithromycin pellets can be also studied by using analytical methods
They are
U-V SPECTROSCOPY
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V. Mridula, Dept. of Pharmaceutics Page 85
HPLC
UV-SPECTROSCOPY
Calibration curve of Telithromycin in phosphate buffer Ph 7.5:
Accurately weighed quantity of Telithromycin (100 mg) was dissolved in little quantity
of phosphate buffer solution, pH7.5, and volume was made up to 100 ml.From this, 1 ml
of solution was pippeted out in to a volumetric flask and volume was made up to 100 ml.
Appropriate aliquots were taken into different volumetric flasks and volume was made up
to 10 ml with phosphate buffer solution, pH7.5, so as to get drug concentrations of 4 to
24 g/ml. The absorbencies of these drug solutions were estimated at max 263 nm.
This procedure was performed in triplicate to validate the calibration curve. The data
were given in Table 11. A calibration curve was constructed as shown in the figure
DOSAGE FORM ANALYSIS BY HPLC METHOD
Chromatography condition
Stationaryphase-hypersil
Mobile phase-buffer – acetonitrile(40:60) ,Sph7.4 with koh solution
Flowrate-1ml/min
Controltemperature-ambient
Detector-280nm
Injectionvolume-20microlitres
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V. Mridula, Dept. of Pharmaceutics Page 86
Preparation of buffer:
Dissolve 2.72g of kH2P04 &0.525 g of k2HPO4 and volume
makeup up to 1000 ml of purified water.
PREPARATION OF STANDARD:
1.40.4 mg of drug dissolved in 20 ml of methanol from this 2ml of solution
dilute.And volume makes up to 50 ml by using mobile phase.
2.Preparation of sample-40 mg of drug equivalent to
20 ml of volumetric flask then add 15 ml of methanol and Sonicate it passed through
micrometer filter take 2ml of filtrate add volume up to 50 ml.
Dissolution studies also takes placed.disintegration also studied.
Comparision of in vitro release profiles were studied.
Preformulation studies also done.
Differential scanning calorimetry and x-ray diffraction studies takes place.
Suitable graphs are obtained.
Suitable excipients are chosen to get sustained action of multiparticulate system of
telithromycin.
We have compared conventional tablet of telithromycin with sustained action pellets
of telithromycin.
In vitro characterisation is also studied.
Its solubility ,stability is also studied.
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V. Mridula, Dept. of Pharmaceutics Page 87
The present study indicates dicrease in dissolution by decreasing its solubility
therefore it shows sustained action.
Telithromycin is anovel drug which shows several advantages than other drugs.
Finally we had used suitable excipients by using suitable equipment and suitable
temperature conditions to get sustained action of multiparticulate system of telithromycin
Finally embedded in hard gelatin capsule.
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7 SUMMARY
The summary of the M. Pharm. dissertation work entitled “SUSTAINED ACTION OFMULTIPARTICULATE SYSTEM OF TELITHROMYCIN EMBEDDED IN HARDGELATIN CAPSULE is given below
Conventional dosage forms, which are prompt release in nature, have been used from
decades for treatment of acute and chronic diseases. To maintain drug concentration in
within the therapeutically effective range it is necessary to take these types of dosage
forms several times a day and which results in the fluctuations in drug levels. Recently,
several technical advancements have been made which results in new techniques for drug
delivery. These techniques are capable of controlling the rate of drug delivery, sustaining
the duration of therapeutic activity and/or targeting the delivery of drug to a tissue.
Controlled release pharmaceutical dosage forms may offer one or more advantages over
conventional (immediate release) dosage forms of the same drug.
The term “sustained release” is known to have existed in the medical and pharmaceutical
literature for many decades. It has been constantly used to describe a pharmaceutical
dosage from formulated to retard the release of a therapeutic agent such that its
appearance in the systematic circulation is delayed and / or prolonged and its plasma
profile is sustained in duration. The onset of its pharmacological action is often delayed
and the duration of its therapeutic effect is sustained.
A multiple unit dosage form could readily separate into sustained release units throughout
the gastrointestinal (GI) tract after ingestion. One of the multiple unit dosage forms is the
pellet, which reduces variation in gastric emptying time and transit time, is less
susceptible to dose dumping, and provides less irritation from high local concentration of
drugs.
Pellets offer a high degree of flexibility in the design and development of oral dosage
forms. They can be divided into desired dose strengths without formulation or process
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V. Mridula, Dept. of Pharmaceutics Page 89
changes and also can be blended to deliver incompatible bioactive agents simultaneously
and/or to provide different release profiles at the same or different release profiles at the
same or different sites in the gastrointestinal tract. In addition, pelletstaken orally,
disperse freely in the GI tract, maximize drug absorption, minimize local irritation of the
mucosae by certain irritant drugs, and reduce inter and intra patient variability.
The objectives of the present investigations are:
1) Preparation of Telithromycin sustained release pellets using different polymers
2) and different techniques
3) Characterization of Telithromycin pellets.
4) In vitro evaluation of telithromycin pellets for the release characteristics
In the present investigation, efforts were made to develop sustained release pellets of
telithromycin for treatment of respiratory disorders .
The drug chosen for the present investigation was telithromycin and which is an
antibiotic . The dose of telithromycin is 300mg and 400mg administered .It is available
in tablet forms .it can taken along with food also. Telithromycin is well absorbed and
extensively metabolized in the liver. On the basis of mass balance studies, at least 92% of
a single dose is absorbed. The plasma elimination half-life is 5 ± 2 hours. Telithromycin
is a white to off- white crystalline solid with a solubility of 572 mg/ml in 0.2 M sodium
chloride solution. These biopharmaceutical and physicochemical properties reveal that
Telithromycin is an ideal candidate to develop into sustained release pellets.
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V. Mridula, Dept. of Pharmaceutics Page 90
The chapter of “Literature Review” contained general concepts and requirements for
sustained release drug delivery system. Advantages and disadvantages of sustained
release drug delivery systems were also discussed. Description about drug selection for
oral sustained release drug delivery systems. General criteria for selection of drug for
sustained release dosage forms were also discussed.
A detailed discussion was done about the pelletization techniques. Each technique was
discussed in detail. A detailed discussion about the drug Telithromycin and other
excipients was also included in the literature review. The discussion on the marketed
products was also included in the literature review.
In order to solve the objectives of this dissertation, suitable analytical method (UV
Spectroscopy)and hplc was established and validated in phosphate buffer solution pH,
6.8.In addition, interference of additives in the estimation was determined. Physical
properties of Telithromycin were also determined.Various binders were tried out for drug
coating on to the non-pareil seeds.
Pregelatinised starch was finalized as the binder and its concentration and the fluid bed
processor parameters were optimized. Seal coating was also performed using the same
binder. The functional coating was done using Eudragit NE30D. The concentration of the
Eudragit was optimized.
A reproducible batch was prepared; evaluation of the pellets was done. Friability,bulk
density, Tap density, drug assay, sieve analysis were performed. Dissolution of the pellets
was done in pH 6.8, phosphate buffer solution. The dissolution was carried on for 24
hours. Accelerated stability studies was also done for 1 month, 40 C and 75 % RH.The
effect of curing of the dissolution of pellets was also studied.
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The results and discussion of different methods of this thesis are described under
different headings using graphs and tables. No interference due to additives in the
estimation of Telithromycin was observed. Various binders were used and finally
pregelatinised starch was finalized as the binder. Dissolution datas of the conventional
tablet is compared with sustained release pellets and the prepared batches was compared.
F1 and F2 were calculated. On the bases of it the concentration of pregelatinised starch
and the polymer Eudragit was optimized.
The formulation was found to be reproducible. The stability studies of the prepared
pellets were done at 400 C and 75 % RH. The dissolution of the stability samples after
month was preformed and the dissolution datas were compared with the conventional
tablet. The F1 and F2 were calculated and the product was found to be stable. The pellets
were cured in hot air oven for 16 hours at 550C and the dissolution was done and the
increase in the rate of dissolution was observed.
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V. Mridula, Dept. of Pharmaceutics Page 92
8. Conclusion
1.Multiparticulate system is very important technique to deliver the recommended dose.
2.It also reduces patience complaince.
3.Telithromycin is a novel antibiotic which acts against bacterial infections.
4.It shows more potent than other antibiotics.
5. Suitable analytical method based on UV-Visible spectrophotometer was developed for
telithromycin . max is 226 nm in phosphate buffer solution, pH 6.8.
6.Eudragit NE 30D in a concentration of 8.6 % w/v was optimized as coating polymer for
150 mg sustained release pellets of Telithromycin.
7.. The effect of agitational intensity of dissolution medium on drug release rate of batch
17 pellets was studied at 50, 100, and 125 rpm.. The release study indicated that rpm 100
is ideal for the studies.
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Telithromycin Pellets
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10. ANNEXURE
ACCEPTED PAPER
S.NO TOPIC JOURNAL AUTHORS
1 Sustained action of
Multiparticulate system of
Telithromycin embeded in
hard gelatin capsule.
International
journal of pharma
world research.
V.Mridula
Dr.K.V.Subramanyam
Ramakhanth
Srujana
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